Phthalocyanines have shown promise for photodynamic therapy (PDT). The overall goals of this Program Project are elucidation of the photochemical, cellular, and tissue-level mechanism(s) of PDT with phthalocyanines and development of new phthalocyanines with improved properties for PDT. Based on demonstrations of efficient photocytotoxicity with phthalocyanines containing axial amine and quaternary ammonium functions, Project I will generate new phthalocyanines with higher or lower polarities, differently positioned or multiple functional groups, varying ring face openness, non-polar face groups, ring or axial modifications, higher mass central elements, different oxidation potentials, and/or deeper red absorptions. Compounds will be characterized chemically and photochemically. Project 2 will test photoactive compounds in cells in culture. Lesions in the plasma membrane, mitochondrion, and nucleus and mechanisms of cell death following PDT will be studied. The potential of two-photon activation will be explored, as will the enhancement of PDT by ionophores and other membrane-active agents. Project 3 will evaluate specific phthalocyanines for their efficacy for photodynamic purging of tumor cells in human bone marrow. Differential response will be sought between normal marrow stem cells and for tumor cell lines which represent malignancies that commonly reside in or metastasize to marrow. Metabolic consequences of the cytotoxic responses will be studied. Project 4 will assess the potential of active phthalocyanines for PDT of solid tumors in vivo. Quantitative evaluation will be made in RIF-1 transplanted tumors, while induced skin tumors will be developed and treated in their own matrix. Measurements will include dark toxicity, immunological responses, pharmacokinetics, normal skin photosensitivity, as well as tumor responses and the contribution of active oxygen species and lipid peroxidation. Core A will operate a light source facility and Core B will provide administrative support for the research. Collaborative approaches will evaluate structures and mechanisms and suggest improvements in photosensitizer design. Better understanding of the photodynamic effects of phthalocyanines and optimized photosensitizers should result.
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